Project Summary Myeloid cells are relatively short-lived, and must be continuously replaced to maintain normal homeostasis. Recent findings showed that variation in immune cell homeostasis exists between individuals. Although non-heritable factors such as age, sex and latent infections can affect variation in immune cell frequencies, data from twin studies suggest a high level of genetic determinism. The object of this proposal is to appreciate the role that host polymorphisms play in steady-state homeostasis using the Collaborative Cross (CC) and Diversity Outbred (DO) animal models that reflect the genetic diversity of an outbred population such as humans. These strains are an ideal resource for high-resolution genetic mapping and will therefore provide a powerful experimental system to test the hypothesis that variation in myeloid cell homeostasis is genetically regulated, and to map the source of the diversity. We first propose to conduct a comprehensive screen of CC and DO strains for systemic and tissue levels of myeloid cells to estimate the diversity resulting from natural genetic variation (Aim 1). Using high-resolution QTL mapping in the DO, we will identify genes that underlie variation in myeloid cell homeostasis and tissue distribution; we will use CC strains for in vivo experimental validation of these genes and mechanistic studies (Aim 2). Altogether exploratory experiments proposed in this project represents a major effort to elucidate the association between genotype and immune cell numbers and will provide a rich resource for interrogating the homeostatic mechanisms governing the balance of immune cells in tissues. !